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United States Patent | 6,193,998 |
Ye ,   et al. | February 27, 2001 |
The efficiency of encapsulating a drug into a liposomal formulation is increased by use of a lipid having a carbon chain containing from about 13 to about 28 carbons during preparation of the liposomes. Preferably the liposomes are multivesicular liposomes.
Inventors: | Ye; Qiang (San Diego, CA); Sankaram; Mantripragada Bhima (San Diego, CA) |
Assignee: | SkyePharma Inc. (San Diego, CA) |
Appl. No.: | 431523 |
Filed: | November 1, 1999 |
Current U.S. Class: | 424/450; 264/4.1; 264/4.3; 424/1.21; 424/9.321; 424/9.51; 424/94.3; 424/417 |
Intern'l Class: | A61K 009/127 |
Field of Search: | 424/450,1.21,9.321,9.51,417,94.3,812 264/41,43 436/829 935/54 |
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Kim Cancer Chemothy. Pharmacol. 33, 187-190, 1993. Kim Cancer Chemothe. Pharmacol. 19, 307-310, 1987. Studies on Phosphatidylcholine Vesicles Formation and Physical Characteristics Huang, Biochemistry, 8:334-352, 1969. Diffusion of Univalent Ions Across The Lamellae of Swollen Phospholipids Bangham, J. Mol. Bio., 13:238-252, 1965. Comparative Properties and Methods of Preparation of Lipid Vesicles (Liposomes) Szoka, et al., Ann. Rev. Biophys. Bioengineering, 9:467-508, 1980. Evaluation of Retinal Toxicity and Liposome Encapsulation of the Anti-CMV Drug 2'-nor-cyclic GMP Shakiba, et al., Investigative Opthalmology and Visual Science, No. 10, 34:2903-2910, Sep. 1993. Fibrin-Enmeshed Tobramycin Liposomes: Single Application Topical Therapy of . . . Frucht-Perry, et al., Cornea, No. 5, 11:393-397, Sep. 1992. Tobramycin Liposomes. Single Subconjunctival Therapy of . . . Assil, et al., Investigative Ophthalmology and Visual Science, No. 13, 32:3216-3220, Dec. 1991. Liposome Suppression of Proliferative Vitreoretinopathy. Rabbit . . . Assil, et al., Investigative Ophthalmology and Visual Science, No. 11, 32:2891-2897, Oct. 1991. Magnetic Resonance Imaging of Rabbit Brain After Intracarotid Injection . . . Turski, et al., Magnetic Resonance in Medicine, No. 2, 7:184-196, Jun. 1988. Filtering Surgery in Owl Monkeys Treated With the Antimetabolite . . . Skuta, et al., American Journal of Ophthalmology, No. 5, 103:714-716, May 15, 1987. Multivesicular Liposomes. Sustained Release of the Antimetabolite . . . Assil, et al., Archives of Ophthalmology, No. 3, 105:400-403, Mar. 1987. Weak Acid-Induced Release of Liposome-Encapsulated Carboxyfluorescein Barbet, et al., Biochimica et Biophysica Acta, No. 3, 772:347-356, May 30, 1984. Preparation of Cell-Size Unilamellar Liposomes with High Captured vol. and Defined Size . . . Kim, et al., Biochim. Biophys. Acta, 646:1-9, 1981. Preparation of Multivesicular Liposomes Kim, et al., Biochem. Biophys. Acta, 728:339-348, 1983. Preparation of Multilamellar Vesicles of Defined Size-Distribution by Solvent-Spherule . . . Kim, et al., Biochim. Biophys. Acta, 812:793-801, 1985. Multivesicular Liposomes Containing Cytarabine Entrapped in the Presence of . . . Kim, et al., Cancer Treat. Rep., 71:705-711, 1987. Multivesicular Liposomes Containing Cytosine 1-.beta.-D-Arabinofuranosylcytosine for Slow-Release Intrathecal Therapy Kim, et al., Cancer Research, 47:3935-3937, 1987. Multivesicular Liposomes Containing Cytosine for Slow Release . . . Kim, et al., Cancer Treat Rep., 71:447-450, 1987. Modulation of the Peritoneal Clearance of Liposomal Cytosine Arabinoside by . . . Kim, et al., Cancer Chemother. Pharmacology, 19:307-310, 1987. Multivesicular Liposomes Containing Bleomycin for Subcutaneous Administration Roy, et al., Cancer Chemother. Pharmacology, 28:105-108, 1991. Prolongation of Drug Exposure in Cerebrospinal Fluid by Encapsulation Into . . . Kim, et al., Cancer Research, 55:1596-1598, Apr. 1, 1993. Direct Cerebrospinal Fluid Delivery of an Antiretroviral Agent Using . . . Kim, et al., Jrnl. of Infectious Diseases., 162:750-752, 1990. Treatment of Leptomeningeal Metastasis with Intraventricular Administration of . . . Chamberlain, et al., Archives of Neurol, No. 3, 50:261-264, 1993. A Slow-Release Methotrexate Formulation for Intrachecal Chemotherapy Chatelut, et al., Cancer Chemother. Pharmacol., 32:179-182, 1993. Quantitative Cerebrospinal Fluid Cytology in Patients Receiving Intracavitary Chemotherapy Russack, et al., Ann. Neurol., 34:108-112, 1993. Extended Cerebrospinal-Fluid Cytarabine Exposure Following Intrathecal Administration of DTC 101 Kim, et al., J. Clin. Oncol., 11:2186-2193, 1993. Liposomes as Carriers of Cancer Chemotherapy: A Review Kim,Drugs, No. 4, 46:618-638, 1993. Extended-Release Formulation of Morphine for Subcutaneous Administration Kim, et al., Cancer Chemother. Pharmacol., 33:187-190, 1993. Production and Size Control of Large Unilamellar Liposomes by Emulsification Ishii, Liposome Technology, 1:111-121, 1993. Structural Properties and Functional Roles of Phospholipids In . . . Cullis, et al., Phospholipids and Cellular Regulation, 1:65-123, 1985. An Extended-Release Formulation of Methotrexate For Subcutaneous . . . Bonetti, et al., Cancer Chemotherapy and Pharmacology., In Press, 1994. Novel Multilayered Lipid Vesicles: Comparison of Physical Characteristics of Multilamellar Liposomes and Stable Plurilamellar Vesicles Grunor, et al., Biochemistry, No. 12, 24:2833-2842, Jun. 4, 1985. |
TABLE 1 Determination of the reproducibility of Cytarabine encapsulation in multivesicular liposomes of varied chain length and saturation Sample [Cytarabine].sup.1 % Encapsulation Lipocrit Mean Particle Preparation mg/mL of compound % Free (in %) Diameter, .mu.m DC16:1 10.0 30.6 4.6 30.7 9.9 Sample 1 DC16:1 10.6 29.6 5.5 30.4 10.0 Sample 2 DC16:1 9.8 30.1 5.4 29.7 10.1 Sample 3 Mean .+-. SD 10.1 .+-. 0.4 30.1 .+-. 0.5 5.2 .+-. 0.5 30.3 .+-. 0.5 10.0 .+-. 0.1 RSD, % of 4.0% 1.7% 9.6% 1.6% 1.0% mean DC18:1 9.4 45.3 2.5 29.1 9.9 Sample 1 DC18:1 9.7 44.7 2.9 29.5 9.9 Sample 2 DC18:1 9.8 43.7 2.7 30.2 9.8 Sample 3 Mean .+-. SD 9.6 .+-. 0.2 44.6 .+-. 0.8 2.7 .+-. 0.2 29.6 .+-. 0.6 9.9 .+-. 0.1 RSD, % of 2.1% 1.8% 7.4% 2.0% 1.0% Mean DC20:1 10.0 57.8 3.0 28.8 11.0 Sample 1 DC20:1 10.2 55.7 2.9 29.8 10.9 Sample 2 DC20:1 9.6 58.8 3.4 28.4 11.1 Sample 3 Mean .+-. SD 9.9 .+-. 0.3 57.4 .+-. 1.6 3.1 .+-. 0.3 29.0 .+-. 0.7 11.0 .+-. 0.1 RSD, % of 3.0% 2.8% 9.7% 2.4% 0.9% Mean .sup.1 [Cytarabine] stands for the concentration of cytarabine in the final liposome suspension.
TABLE 2 Effect of phospholipid chain length on encapsulation efficiency of cytarabine in multivesicular liposomes % Encapsulation % Lipocrit Phospholipid [Cytarabine].sup.1 of compound Free (in %) Mean Saturated PC DC12:0PC 0.4 0.2 -- -- -- DC14:0PC 6.2 31.1 0.9 22.0 9.0 DC16:0PC 10.7 54.6 1.3 28.5 9.8 DC18:0PC 10.2 56.9 0.8 26.8 9.7 Unsaturated PC DC16:1PC 10.1 30.1 5.2 30.3 10.0 DC18:1PC 9.6 44.6 2.7 29.6 9.9 DC20:1PC 9.9 57.5 3.1 29.0 11.0 .sup.1 [Cytarabine] stands for the concentration of cytarabine in the final liposome suspension.
TABLE 3 Effect of varying the chain length of the phospholipid on encapsulation efficiency for cytarabine encapsulation into multivesicular liposomes % Encapsulation Lipocrit Mean Phospholipid [Cytarabine].sup.1 of compound % Free (in %) Particle DOPG-DC16:1PC 7.4 36.8 2.1 25.8 9.0 DOPG-DC18:1PC 9.6 47.3 1.7 30.5 10.0 DOPG-DC20:1PC 10.7 53.2 2.3 36.6 11.2 .sup.1 [Cytarabine] stands for the concentration of cytarabine in the final liposome suspension.
TABLE 4 Effect of phospholipid chain length on encapsulation efficiency of morphine into multivesicular liposomes [Morphine].sup.1 % Encapsulation Lipocrit Mean Particle Phospholipid (mg/mL) of compound % Free (in %) Diameter (.mu.m) Saturated PC DC14:0PC 13.9 38.7 1.7 27.6 9.2 DC18:0PC 20.1 55.6 0.7 32.9 9.5 Unsaturated PC DC16:1PC 12.8 35.5 7.7 20.2 9.8 DC18:1PC 21.5 59.8 1.3 36.5 9.5 DC20:1PC 24.6 68.3 0.9 37.6 9.6 .sup.1 [Morphine] stands for the concentration of morphine in the final liposome suspension
TABLE 5 Effect of phospholipid chain length on efficiency of encapsulating leuprolide into multivesicular liposomes [Leuprolide].sup.1 % Encapsulation Lipocrit Mean Particle Phospholipid (mg/mL) of compound % Free (in %) Diameter (.mu.m) Saturated PC DC12:0PC 2.0 9.8 5.9 35.8 10.9 DC14:0PC 2.0 12.3 3.1 35.8 13.2 DC16:0PC 1.6 20.1 10.9 35.7 15.9 DC18:0PC 2.4 46.7 3.5 37.4 15.5 DC20:0PC 2.6 50.7 2.9 40.1 15.1 Unsaturated PC DC18:1PC 4.1 55.4 2.2 39.3 9.7 DC22:1PC 3.4 83.3 1.1 56.1 14.3 .sup.1 [Leuprolide] stands for the concentration of leuprolide in the final liposome suspension.
TABLE 6 Effect of chain length on efficiency of encapsulating cytarabine in multilamellar liposomes [Cytarabine].sup.1 % Encapsulation Lipocrit Mean Particle Phospholipid (mg/mL) of compound % Free (in %) Diameter (.mu.m) DC14:0PC 1.03 6.5 1.2 14.0 4.7 DC16:0PC 1.85 11.6 1.1 16.7 4.1 DC18:0PC 3.54 44.2 0.4 24.6 4.7 .sup.1 [Cytarabine] stands for the concentration of cytarabine in the final liposome suspension